A newly published article in the Journal of Clinical Oncology has demonstrated an association between treatment with androgen deprivation therapy (ADT) and risk for diagnosis with Alzheimer’s disease among prostate cancer patients at an average of 3 years of follow-up. However, … quite what this really means is still very debatable.

We have known for years that there is an association between long-term treatment with ADT and risk for impact on mental function — inclusive of difficulties with concentration, focus, and multi-tasking. We also know that many people today are diagnosed as having Alzheimer’s disease when they show signs of age-related mental dysfunction. What we don’t know is what percentage of those patients really have Alzheimer’s disease (characterized by a specific type of amyloid plaque in the brain, caused by clumping of β-amyloid) and what percentage have other, quite “normal” forms of age-related mental disorder. It’s not as though everyone diagnosed with Alzheimer’s disease has a brain biopsy to confirm the diagnosis. And for many doctors, patients, and family members it is a great deal more “socially acceptable” to be told that the patient has “a disease” than to be told that the patient has age-related dementia. (Your sitemaster wishes to be very clear that age-related dementia runs in one side of his family, and the individuals concerned did not have Alzheimer’s disease.)

Nead et al. report data from a detailed, retrospective analysis of data based on the electronic medial records of 16,888 men diagnosed with prostate cancer treated at Stanford University and Mt. Sinai hospitals here in the USA. They looked very specifically at all mentions of drug use and disease concepts within the patients’ clinical notes and found the following:

2,397/16,888 prostate cancer patients (14.2 percent) received ADT over an average (median) follow-up period of 2.7 years.

Two different types of statistical analysis supported an association between treatment with ADT and a subsequent diagnosis with Alzheimer’s disease.

In addition, risk for diagnosis with Alzheimer’s disease increased with increasing duration of ADT (P = 0.016), with men on ADT for > 12 months being at more than twice the risk for Alzheimer’s than prostate cancer patients who never received ADT.

The authors conclude that their

results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer’s disease in a general population cohort.

Researchers can’t prove a direct cause-and-effect link between ADT and Alzheimer’s in an observational study like this. Some other unknown variable might be influencing the results.

and

Given that it’s a first-time association in a retrospective analysis, this study helps inform future research but it’s not appropriate at this point to make treatment decisions off of it.

According to Keith Fargo, PhD, director of scientific programs and outreach for the Alzheimer’s Association, androgens do seem to assist in the maintenance of low levels of circulating β-amyloid in a person’s bloodstream. This might help to explain an association between ADT and risk for Alzheimer’s. However, Dr. Fargo also states that:

I don’t think any doctors are going to make different decisions based on this single study. If your doctor has put you on this medication for your prostate cancer treatment, you should continue it. Consult with your physician, but don’t stop taking your medication based on a study like this.

We are going to need a good deal more information before we know to what extent ADT is actually causing Alzheimer’s disease … or indeed whether that is actually happening at all. A starting point for such research might be by looking for levels of β-amyloid plaques at autopsy in the brains of men with prostate cancer who died after being on ADT (but not other drugs) for varying periods of time (whether or not they were diagnosed with Alzheimer’s).

7 Responses

Treatment with dutasteride (Avodart) is a form of ADT but is not one of the forms of ADT that would have been encompassed in the study by Nead et al. Furthermore, I am not aware of any association between long-term treatment with Avodart or other drugs like Avodart (e.g., finasteride/Proscar) and significant changes in mental function.

Great! Now I have to worry about getting Alzheimer’s in addition to the advanced metastatic prostate cancer. But then again, if I do get Alzheimer’s, I’ll be able to finally forget about the cancer, eating away at my body and my soul. I guess that there’s a silver lining to every cloud (sarcasm).

The concern raised by this study has been around for a long time. As a patient on long-term intermittent ADT (actually ADT3, Lupron plus bicalutamide/Casodex or flutamide in the fourth round, plus finasteride and later dutasteride/Avodart), I have paid some attention to the issue of whether there is a worrisome cognitive side effect of ADT, never seeing a hot lead, and I’m thinking this paper, though legitimately keeping the concern alive, is not a hot lead either.

What I was hoping to see in the abstract or commentary was that age had been ruled our as a confounding explanation of the association. Unfortunately, age is not addressed. The problem raised by age is that men given ADT are typically older, and for a disease that is usually diagnosed in older men, with ADT, compared to all patients with prostate cancer who are not on ADT, you generally are going to get an older set of the older men, which raises a quite plausible explanation that the age-related dementia mentioned by Sitemaster is behind all or most of the association found in the study.

Perhaps age is addressed in the complete paper, but I suspect not based on this text from the second link: “Patients who had been treated with ADT had an 88 percent increased risk of an Alzheimer’s diagnosis within an average three-year follow-up period, compared to those who didn’t receive the hormone therapy, the researchers found.” That sentence pretty much states that the research team simply compared those who were on ADT to those who were not, with no adjustment for age.

I am also frustrated that the authors did not give us the absolute level of risk of Alzheimer’s for the non-ADT patients, or, because that is probably unknowable, the absolute risk of Alzheimer’s in the general population as a convenient and fairly valid proxy. If the absolute risk were 1 in a million, then an 88% risk increase would not be worth thinking about. On the other hand, if the absolute risk were 1 in 10, that would command our attention. Whenever I see study results that fail to tell us the absolute risk but only give the relative risk, I suspect the authors failed to find anything worthy of interest but are using the relative risk figure to garner unwarranted attention.

Other explanations may partly explain the results. One reality is that a many of us on ADT experience hot flashes and/or sweating at night, with perhaps half of those affected having to deal with consequent disturbed sleep. That was my experience, especially during the first round when I was in the process of learning how to cope. While there are ways of countering the flashes/sweats, it is clear that some of us do not use needed countermeasures — likely due to unawareness, and resulting fatigue could contribute to or be mistaken for symptoms of Alzheimer’s.

Another issue is the extent to which patients were or were not on intermittent ADT, as patients on intermittent ADT with sufficiently lengthy vacations often enjoy many months free of ADT side effects, while that is not true for those on continuous ADT. A number of guideline groups favor intermittent ADT where possible (such as for patients achieving a sufficiently low PSA nadir and who are not metastatic).

I was on ADT to deal with a challenging, once life-threatening case for 31 months and off for 34 months for my first round, on for 19 months and off for 21 for my second round, on for 19 months and off for 29 months for my third round, and on for 18 months and off, after a curative radiation attempt in March/April 2013 with cessation of supportive ADT in April 2014, for 20 months and counting to the present (current PSA < 0.05, lower limit of this version of the test).

PS: The complete paper should give the number of patients diagnosed with Alzheimer’s in both the non-ADT and ADT groups, which would give us some handle on the absolute risk through comparison to the numbers of patients in the study who were not diagnosed with Alzheimer’s. I wish the authors had stuck the numbers for Alzheimer’s diagnoses for both groups in the abstract itself.

Just checking back due to the new article Sitemaster posted today. I’m still doing fine with a PSA of < 0.05, and I am not experiencing signs of dementia or Alzheimer's. (That's in my humble opinion; my wife might disagree.)

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